SUMMARY: Allogeneic blood or marrow transplantation (alloBMT) remains the only curative treatment for many patients with malignant and non-malignant disorders. The primary challenges limiting the success and scope of alloBMT have included: barriers to donor availability, non-relapse mortality (NRM), acute and chronic graft- versus-host disease (GVHD) and relapse of underlying malignancy. Through the implementation of post- transplantation cyclophosphamide (PTCy), translational research initiatives completed at the Johns Hopkins Kimmel Cancer Center have successfully overcome nearly all of these challenges. The administration of PTCy ensures that nearly every patient in need of a BMT will have a suitably matched, related or unrelated, donor. Moreover, when administered following reduced intensity conditioning (RIC) regimens PTCy allows safe, haploidentical (haplo) BMT to be conducted in patients up to a least age 75. Significant reductions in non-relapse mortality (NRM) and chronic GVHD have underscored the risk of relapse as the major challenge facing our patients with malignant conditions. Hence novel strategies to anti-tumor effects post-BMT are desperately needed. Recent breakthroughs in cancer biology and the analysis of anti-tumor immunity conclusively demonstrate that the human immune system plays an active role in the surveillance and treatment of cancer. Patients with cancers that are not responding to chemotherapy or immunotherapy have an immune system that is either exhausted or lifeless. AlloBMT provides a patient with a healthy and functional immune system that when augmented may be capable of responding more productively to immunogenic tumor antigens. Indeed, while donor-derived, tumor responses are known to contribute to disease control after BMT, they are associated with deleterious GVHD. We postulate optimal graft-versus-tumor (GVT) activity needs to be tumor specific / selective. Such activity would be enhanced by the establishment of tolerance to hematopoietic cell antigens (limit GVHD) while harnessing (and augmenting) the response of donor-derived T cells targeting tumor neoantigens (optimize GVL activity). To this end, the central hypothesis of this project is that the efficacy of alloBMT can be improved by developing methods to target donor T cells against antigens selectively or uniquely expressed by tumor tissue. Our PTCy platform is uniquely suited to exploit this scenario, which underscores the innovation of this proposal: to boldly (and safely) broaden the scope of RIC haploBMT as an effective immunotherapy platform for patients with high-risk, poorly responsive solid tumors including sarcomas (Aim 1), castration-resistant prostate cancer (Aim 2) and HPV+ squamous cell cancers of the head and neck (Aim 3) who have no other chance for cure. If successful, the impact of this work will be extremely high; the principle of biasing the donor T cell repertoire toward tumor-specific antigens will open the door for optimizing the role of BMT to treat all human malignancies.